A new perspective of atherogenesis has gradually emerged that views atherosclerosis as a chronic inflammatory process and emphasizes potential contribution of mononuclear leukocytes and their products to the formation and progression of arterial lesions. Endothelial cells are also potent effector cells in inflammatory and immune reactions. This proposal examines the cellular and molecular mechanisms by which endothelial cells are activated to express a proinflammatory phenotype as evidenced by surface expression of adhesion proteins that bind leukocytes. We will focus on the cytokine-induced protein, vascular cell adhesion molecule-1 (VCAM-1), that mediates mononuclear leukocyte adherence to endothelium in vitro. We propose to: 1) characterize the cis- and trans-acting elements that regulate VCAM-1 expression in cultured human endothelial cells; 2) define the signal transduction pathways involved in induction of endothelial VCAM-1 by tumor necrosis factor-alpha (TNF) and interleukin-1 (IL-1) in vitro; 3) determine effect of infection by human herpesviruses on VCAM-1 expression by cultured human endothelial cells; and 4) determine the surface expression of VCAM-1 by endothelium in human atherosclerotic lesions.